Innovations in transcranial sonothrombolysis have been made by Alexandrov, Holland, Culp, Voorhees, Vortman, Chopra, Unger, Baron, Furuhata, Horzewski, Hansmann, Smith, Browning, Daffertshoffer, Lauer, and by others. However, all studies to date have been problematic in one way or another. The device of the invention differs from the devices used in the earlier CLOTBUST studies (Alexandrov et al 2004a & 2004b) and in studies by Sharma et al (2008a & 2008b) and Cintas (2002) in that those studies used a single diagnostic transducer unit manually operated by a sonographer to establish a preferred orientation, and the transducer unit was then typically locked into place using a cumbersome support frame. Alexandrov recently summarized the art in that, “One of major limitations of this technology that there are no reliable head frames for transducer fixation, and most studies are to be carried out hand-held” (Tsivgoulis 2007 J Clin Neurol 3:1-8). The head frames generally have a skeleton of surgical steel and are weighty and opaque to CT or MRI scanners.
Because the transducer units of the art must be carefully placed by sonographic imaging of the cerebral vasculature, generally with Doppler imaging, valuable time is lost. A solution to this problem as described here is to position a headset of the invention without diagnostic imaging as a guide, but instead by reference to guide, but instead using mechanical alignment guides by reference to external craniological landmarks and to use non-focused ultrasound transducers. Craniological landmarks are selected that define a reference plane tangential to the anterior and posterior cingulate processes, the reference plane with x, y and z coordinates, and thus the location of the cerebrovascular nexus where most strokes occur. The need for sonographer-controlled aiming is eliminated by preset angulation of each transducer relative to the external landmarks and the reference plane defined thereby.
Also consequent to the use of trained operators to set up devices for transcranial sonothrombolysis, there is in the art a general lack of consistency from operator to operator and from institution to institution. The reproducibility of transcranial ultrasound would be increased by provision for an autonomous apparatus that is configured to deliver a prescribed regimen of ultrasound with a fixed anatomical orientation. In order to relieve the need for a precise location of a clot, a solution to the problem of reproducibility is to provide multiple transducer arrays on a headset that is positioned as described above, so that the relationship of the transducer arrays to the cerebral vasculature is established by reference to external craniological landmarks, and to then insonate in a way that is generally safe, eliminating the need for a diagnostic study. In a preferred embodiment, the apparatus may be used where hemorrhage is present or is likely to occur, as is not infrequently the case in stroke and particular in stroke that has been treated with anticoagulants or thrombolytic drugs. In a first embodiment of the inventive apparatus, the autonomous insonation regime includes cyclical repetition of trains of pulses of ultrasound, where each cyclical repetition of pulse trains is a “metapulse” having a vectored and temporal distribution of individual pulse trains, with provision for alternating from transducer to transducer and limiting duty cycle so that no assisted cooling is required. The amplitude of ultrasound emitted by each transducer may be adjusted to compensate for differences due to transducer-to-transducer variability in manufacture, a technological advance in the art.
Portability remains a problem. Several features of the apparatus of the invention operate in synergy to enable the device to be transported with the subject without interrupting insonation. Alternatively the subject may walk while wearing the apparatus. By providing a lightweight power supply in a pocket-sized housing attached to the headset by a cable, the need for attachment to a stationary power supply is eliminated. Low power consumption for extended use is achieved by reducing the duty cycle of the insonation and by configuring emissions in the form of pulse trains having a pulse repetition frequency (PRF) and a pulse train repetition frequency (PTRF). Elimination of energy-consuming cooling means is made possible by alternating actuation of individual transducers at a cyclical frequency so that heat may dissipate during pulse intervals without need for assisted cooling, such as by fans or circulating coolant.
By making the headset from a lightweight and X-ray translucent material, and by configuring ultrasonic emissions from the headset transducer arrays for low power consumption, the apparatus becomes fully portable, may be transported with the patient, and operation of the apparatus need not be interrupted while the subject is, for example, inserted into a diagnostic machine for computerized tomography (CT). The option of beginning and continuing insonation while awaiting definitive diagnosis by angiographic CT is made possible by tethering the electronics and power supply away from the headset assembly at the end of a cable so that diagnostic imaging is not interfered with and by use of plastic structural members. Because transverse sections are commonly used in imaging to visualize the cerebral arterial nexii, in one embodiment the transducer array is mounted supracranially so that imaging may be performed without interference.
The option of portable extended delivery of transcranial ultrasound for sonothrombolysis has been a longstanding need but has not previously been realized. The apparatus of the invention is configured for continuous autonomous operation for 2 hrs, for 4 hours, for up to 12 hours, or for longer with intermittent operation, without operator intervention or recharge, and hence may be used non-invasively in stroke prophylaxis, as a follow-up to administration of thrombolytic drugs, and for other neurovascular conditions where persistent exposure to low amplitude ultrasound is desirable.
Tools for non-invasive sonothrombolysis, as known in the art, remain experimental, and have not yet resulted in changes to the basic standard of care for stroke or dramatically improved the prognosis. Recent clinical trials supplementing r-tPA with transcranial ultrasound resulted in an unacceptably high incidence of intracranial hemolysis (ICH) and the trials were stopped. Since then, no advance in the clinical use of transcranial sonothrombolysis has been reported.
Importantly, centralized stroke centers are currently available in only 3% of stroke cases, and mortality and morbidity following advanced diagnosis and treatment—absent sonothrombolysis—have improved by only 20% overall—even with the most advanced care. Each year in the United States, 700,000 strokes occur, more than 150,000 deaths are caused by strokes, and many strokes are debilitating for those who survive. Thus there is a need for new solutions and improvements in transcranial insonation that overcome the disadvantages described above. The risks of invasive treatments, administration of r-tPA among them, continue to outweigh potential benefits in the estimation of many physicians, and there is a long-felt and unmet need for an apparatus for stroke care having improved efficacy; an apparatus that is non-invasive, non-surgical, and safe.